Influenza is a highly infectious disease caused by rapidly mutating influenza viruses. It is easily transmitted and spreads around the world in seasonal epidemics, affecting 10-20% of the total population annually. According to the World Health Organization (WHO), 250,000-500,000 people die annually of seasonal influenza-related causes during epidemic outbreaks. In the USA alone more than 200,000 people are hospitalized with seasonal influenza in a typical year. Influenza infection may be mild, moderate or severe, ranging from asymptomatic through mild upper respiratory infection and tracheobronchitis to a severe, occasionally lethal, viral pneumonia. The infection is associated with pulmonary and cardiovascular complications leading to high morbidity and mortality rates, affecting mainly at-risk populations such as toddlers, elderly and individuals with chronic medical conditions.
Influenza viruses have two important immunological characteristics that present a challenge to vaccine preparation. The first concerns genetic changes that occur in the surface glycoproteins every year, referred to as “antigenic drift”. This antigenic change produces viruses that elude resistance elicited by existing vaccines. The second characteristic of great public health concern is that influenza viruses, in particular influenza A virus can exchange genetic material and merge. This process, known as “antigenic shift”, results in new strains different from both parent viruses, which can be lethal pandemic strains.
Of the three types of influenza viruses, Influenza A and Influenza B are responsible for approximately 80% and 20% of influenza disease in humans, respectively, while influenza C viruses do not infect humans. Influenza A viruses are characterized by many sub-strains and by species specificity and are considered to be the major cause of widespread seasonal epidemics and of pandemics, due to the frequent antigenic drifts and shifts of the Hemagglutinin (HA) and Neuraminidase (NA) surface proteins. Following antigenic changes, infection via virus strains which are unrecognized by the immune system may result in a reduced immune response by the infected individual, where more significant changes will yield less effective stimulation of the body's immune defenses. Antigenic drifts or shifts can trigger respective influenza epidemics or pandemics, as experienced with the recent Avian and Swine Flu pandemic strains.
Immunization towards influenza virus is limited by the antigenic variation of the virus. The influenza vaccines currently available are the following: whole virus vaccines—inactivated or live-attenuated virus; split virus vaccines (virus fragments); subunit vaccines or purified antigens (in which the surface proteins Hemagglutinin (HA) and Neuraminidase (NA) are purified from other virus components); and virosomal vaccines: synthetic virus-like particles with embedded HA and NA virus surface proteins.
To date, commercially available influenza vaccines contain influenza A and B antigens that are annually selected according to predictions of the strains to be most prevalent during the peak influenza season. However, due to the mismatch between the strains included in the vaccine and those actually circulating, these strain-specific vaccines often have relatively poor clinical efficacy. In addition, such immunization methods require preparation of new vaccine formulations on an annual basis. Thus, a vaccine recognizing multiple virus strains would be more cost effective and would further increase patient compliance and enhance global health prospects.
PCT International Publication WO 2009/016639 to some of the inventors of the present invention discloses influenza multi-epitope polypeptides and vaccines comprising a plurality of influenza virus peptide epitopes wherein each epitope is present at least twice in a single polypeptide.
The Multimeric-001 (M-001) vaccine consists of nine conserved linear epitopes arranged as three repetitions of each and prepared as a single, recombinant protein expressed in E. coli. These epitopes are common to the vast majority of influenza virus strains, regardless of their antigenic drifts and shifts. Consequently, M-001 is expected to provide immunity-based protection against future virus strains as well. The chosen epitopes activate both the humoral and cellular arms of the immune system, creating maximal efficacy in antigen-stimulated resistance to infection (Adar Y et al. Vaccine, 2009; 27, 2099-2107).
Previous experimental studies performed in young and aged mice and rats, indicate that administration of the epitopes included in the Multimeric-001 vaccine leads to efficient cross-strain protection against influenza. Both humoral and cellular immune arms were activated in mice that received three vaccinations at three week intervals. Antibodies raised against M-001 demonstrated cross-strain influenza recognition, despite variations in the outer proteins of each strain. Moreover, lysis of MDCK cells infected with the influenza virus was recorded upon incubation with anti-M-001 antibodies, suggesting a mechanism of action for the humoral response to the vaccine.
The significant results obtained with various animal models and the safety parameters observed in the repeated toxicology study have paved the way toward, and provided the foundation for, clinical trials in humans.
The M-001 vaccine has been administered in both adjuvanted and non-adjuvanted formulations. A Phase I/II clinical trial assessing the safety and efficacy of M-001 in young, healthy volunteers was recently completed. Doses of 125-500 μg adjuvanted or non-adjuvanted vaccine proved safe and well tolerated. In addition, the adjuvanted 500 μg M-001 dose induced most significant immune responses, when compared to the other treatment groups.
Potential Multimeric-001 vaccine-related toxicity was evaluated in toxicology studies. Both M-001 vaccine formulations (adjuvanted and non-adjuvanted) repeatedly IM administered at the maximal human dose, proved to be safe.
Thus there is an unmet need for improvement of the protective effect of seasonal vaccines against influenza by an influenza peptide epitope-based vaccine which can induce humoral and cellular responses that are long-lasting with broad specificity.